It is important to consider several additional guidelines for efforts to increase our knowledge of specific gene variants that relate to alcohol sensitivity. First, studies of high stimulation or low LR need to control for the strong effects of ALDH2,2 and ADH1B genotypes, as these could obscure the effects of other genetic contributors to alcohol responses. Second, the impact of any phenotype on adverse alcohol outcomes is likely to operate through many genes and through environmental and attitudinal characteristics. Thus, whenever possible, studies should evaluate more than one gene variant at a time and search for G × G and G × E additive and mediational interrelationships (Olfson et al., 2014; Schuckit and Smith, 2017; Schuckit et al., 2017b). Third, in light of the likely small effect for any one variant when studied across families, investigators should consider evaluating gene effects vertically within families, as some variants might be seen in a third or more of members of any one family (Choquet et al., 2013) but be observed in a small proportion of the general population. Fourth, for most gene
